The Zonulin-transgenic mouse displays behavioral alterations ameliorated via depletion of the gut microbiota

Miranda-Ribera, Alba; Serena, Gloria; Liu, Jundi; Fasano, Alessio; Kingsbury, Marcy A.; Fiorentino, Maria

doi:10.1080/21688370.2021.2000299

Cited by 9 publications

(17 citation statements)

References 183 publications

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“…We investigated if BC administration in drinking water ad libitum would modulate/affect: (1) microbiota in WT and Ztm and/or increase intestinal microbial eubiosis in Ztm mice and (2) behavior in WT and Ztm and/or ameliorate behavioral changes previously reported in Ztm mice [39].…”

Section: Methodsmentioning

confidence: 99%

“…Increased antigen trafficking through a dysfunctional intestinal barrier due to dysbiosis allows harmful substances from the intestinal lumen to enter the bloodstream [19,25], subsequently triggering immune cell activation that may lead to systemic inflammation [30][31][32][33][34]. Defects in the intestinal barrier function, including dysbiosis, have been found in several psychiatric disorders, such as autism spectrum disorder (ASD) [35][36][37], schizophrenia [35,[38][39][40], and anxiety disorders [41][42][43], which have been associated with increased inflammation [40,[44][45][46][47][48][49]. Furthermore, a dysfunctional MGBA associated with neuroinflammation has been reported in ASD and attention deficit hyperactivity disorder (ADHD) [12,[50][51][52][53][54][55].…”

Section: Introductionmentioning

confidence: 99%

“…Although we do not yet fully understand the functional significance of the symbiotic relationship between the host and the microbiome, especially in the context of brain health, several tools and animal models have been invaluable in allowing researchers to constantly narrow the gaps in understanding of the MGBA. One of these is the zonulin-transgenic mouse (Ztm) model, which is characterized by increased intestinal permeability, dysbiotic intestinal microbiota, activation of the innate immune system, and mild hyperactivity [27,39]. A better understanding of the mechanism of the MGBA involving the neuro-immune system might offer a new approach to the treatment of mental disorders.…”

Section: Introductionmentioning

confidence: 99%

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Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice

et al. 2022

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The microbiota–gut–brain axis (MGBA) involves bidirectional communication between intestinal microbiota and the gastrointestinal (GI) tract, central nervous system (CNS), neuroendocrine/neuroimmune systems, hypothalamic–pituitary–adrenal (HPA) axis, and enteric nervous system (ENS). The intestinal microbiota can influence host physiology and pathology. Dysbiosis involves the loss of beneficial microbial input or signal, diversity, and expansion of pathobionts, which can lead to loss of barrier function and increased intestinal permeability (IP). Colostrum, the first milk from mammals after birth, is a natural source of nutrients and is rich in oligosaccharides, immunoglobulins, growth factors, and anti-microbial components. The aim of this study was to investigate if bovine colostrum (BC) administration might modulate intestinal microbiota and, in turn, behavior in two mouse models, wild-type (WT) and Zonulin transgenic (Ztm)—the latter of which is characterized by dysbiotic microbiota, increased intestinal permeability, and mild hyperactivity—and to compare with control mice. Bioinformatics analysis of the microbiome showed that consumption of BC was associated with increased taxonomy abundance (p = 0.001) and diversity (p = 0.004) of potentially beneficial species in WT mice and shifted dysbiotic microbial community towards eubiosis in Ztm mice (p = 0.001). BC induced an anxiolytic effect in WT female mice compared with WT female control mice (p = 0.0003), and it reduced anxiogenic behavior in Ztm female mice compared with WT female control mice (p = 0.001), as well as in Ztm male mice compared with WT BC male mice (p = 0.03). As evidenced in MGBA interactions, BC supplementation may well be applied for prophylactic approaches in the future. Further research is needed to explore human interdependencies between intestinal microbiota, including eubiosis and pathobionts, and neuroinflammation, and the potential value of BC for human use. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice

et al. 2022

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“…Other indirect mechanistic pathways such as gastrointestinal permeability linked with the gut–brain axis are more likely to be responsible, as exemplified by zonulin transgenic mice which display neurological abnormalities improved by antibiotic depletion of gut microbiota. 10 Future studies should further investigate these pathways and the relationship between zonulin and the severity of neurological disease.…”

Section: Tablementioning

confidence: 99%

Zonulin and blood–brain barrier permeability are dissociated in humans

Stuart

Varatharaj

Winberg

et al. 2022

Clinical & Translational Med

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Dear Editor, Zonulin, or prehaptoglobin-2, mediates intestinal permeability in coeliac disease through the regulation of epithelial tight junctions. 1 Tight junction breakdown at the blood-brain barrier (BBB) is a common pathological finding in neurological disease, 2 and several in vitro and preclinical in vivo studies have suggested that zonulin plays a role in modulation of BBB permeability, 3-6 yet using multiple methods, we here consistently find that zonulin plays a negligible role in human BBB permeability.Zonulin is a member of the MASP (mannose-binding lectin-associated serine protease) family of proteins, and elevated serum zonulin levels have been reported in a number of neurological conditions such as multiple sclerosis 7 and Alzheimer's disease. 8 The significance of zonulin upregulation in these neurological diseases is not certain. Specifically, it is not clear whether zonulin is an epiphenomenon, or has an effect on the brain, whether directly or mediated through the gut-brain axis.To study the association between zonulin and BBB permeability in healthy individuals and patients with neurological disease, we employed two techniques to measure permeability across a range of molecular weights: Q Alb , or the quotient of cerebrospinal fluid to serum albumin (60 000 Da) in Study A and dynamic contrastenhanced magnetic resonance imaging with gadobutrol tracer (600 Da) in Study B (Supplemental Methods). Participant characteristics are shown in Table 1.Out of a total of 217 cases (including people with neurological conditions and control individuals) across both studies, 58 (27%) individuals tested negative for serum zonulin using a novel enzyme-linked immunosorbent assay (ELISA) (Supplemental Methods). Serum zonulin concentration followed a non-Gaussian distribution with a range of 0-11 µg/ml. There were no effects of sex, age or disease status (disease vs. control) on zonulin concentrations (analysis of covariance, F(3,216) = 1.06, p = .37). In order to assess zonulin using a complementary dual approach,This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Основываясь на том, что аналогичные эффекты наблюдались в системе in vitro на клетках Сасо-2, можно предположить возможный механизм, по которому ось "кишечник -мозг" (КМО) вовлекается в патогенез нейровоспалительных заболеваний [76]. Например, увеличенная кишечная проницаемость позволяет антигенам пересечь кишечный эпителий и с потоком крови через нарушенный ГЭБ войти в мозг и воздействовать на его функции [80] (рис. 2).…”

Section: участие зонулина в мозговых процессахunclassified

Zonulin — regulation of tight contacts in the brain and intestine — facts and hypotheses

Naryzhny

Legina

2022

BIOMED KHIM

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In recent years, the interrelationship between the brain and the gut has become an area of high scientific interest. The intestine is responsible not only for digestion, as it contains millions of neurons, its own immune system, and affects the emotional and cognitive processes. The relationship between the gut and the brain suggests that the processes carried out by the gut microbiota play a significant role in the regulation of brain function, and vice versa. A special role here is played by intercellular tight junctions (TJ), where the zonulin protein holds an important place. Zonulin, an unprocessed precursor of mature haptoglobin, is the only physiological modulator of intercellular TJ that can reversibly regulate the permeability of the intestinal (IB) and blood-brain (BBB) barriers in the human body. BBB disruption and altered microbiota composition are associated with many diseases, including neurological disorders and neuroinflammation. That is, there is a gut-brain axis (GBA) — a communication system through which the brain modulates the functions of the gastrointestinal tract (GIT) and vice versa. GBA is based on neuronal, endocrine, and immunological mechanisms that are interconnected at the organismal, organ, cellular, and molecular levels.

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The Zonulin-transgenic mouse displays behavioral alterations ameliorated via depletion of the gut microbiota

Cited by 9 publications

References 183 publications

Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice

Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice

Zonulin and blood–brain barrier permeability are dissociated in humans

Zonulin — regulation of tight contacts in the brain and intestine — facts and hypotheses

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